This chapter analyzes ongoing European Union (EU) policy changes that affect Big Science and Research Infrastructures. These changes are part of a broader EU political agenda to strengthen the EU’s global position, facilitate growth and enhance coordination among EU member states. Important initiatives for Big Science and Research Infrastructures include the launch of large-scale research projects, support for e-infrastructures and the development of EU policy towards Research Infrastructures in the framework of the European Research Area initiative. To illustrate these EU policy changes, the chapter uses the example of the Human Brain Project – a large-scale research project that is turned into a research infrastructure. The chapter demonstrates that EU policy for Research Infrastructures supports a model of differentiated integration where a number of EU member states and non-members collaborate. While this model has the advantage of bringing together countries interested in particular Research Infrastructures, it can also present challenges when supranational projects are turned into Research Infrastructures.